This amended application proposes to continue a multi-center collaborative investigation of the genetic aspects of Long QT syndrome (LQTS). The application capitalizes on an International LQTS Registry maintained by this research group that contains more than 700 proband- identified families. The application has four Specific Aims: 1) to map new genetic loci for LQTS and to clone and characterize the LQTS-causing genes; 2) to identify new intragenic, mutations involving the four known ion channels accounting for 50 percent of LQTS; 3) screen probands and family members for known LQT gene mutations to expand the number of identified carriers and; 4) to explore for modifier-gene loci in families already identified with a mutant LQT gene. Functionally, there are three components of the grant: 1) a genotype section with two molecular genetic research labs; 2) a statistical genetics section that will coordinate analyses related to modifier-gene influences on clinical severity in individuals with LQT mutations and; 3) a coordination and data center to provide data management and coordination between the other components of this program.